Pain serves important functions in warning of danger, but chronic pain can have devastating effects on the quality of life, It has been estimated that in the United States alone, about 2 million people are incapacitated by pain at any given time. A better understanding of pain receptors and their modulation by endogenous peptides could lead to the development of new drugs to better treat pain. The role of the acid-sensing ion channels (ASICs) as mediators of pain reception is still unclear, but it is known that neuropeptides can modulate the sensitivity of these channels. The endogenous peptide, neuropeptide FF (NPFF), is known to modulate pain pathways. Our long-term goal is to test the hypothesis that NPFF modulates pain by acting directly on sensory ion channels to regulate their response to painful stimuli. We will develop pharmacological tools needed to distinguish the direct effects of NPFF and related peptides on ion channels from their indirect effects (mediated through G-protein-linked receptors). NPFF has been shown to directly modify the response of the dorsal root ganglion acid-sensing ion channel to acid, and a G-protein-f inked receptor for NPFF has recently been identified that could mediate indirect effects. Since acid-sensing ion channels are thought to participate in the transduction of painful responses to tissue acidosis, their direct modulation could represent a novel peripheral mechanism whereby NPFF might regulate pain pathways. The main aim of this proposal is to develop NPFF agonists and antagonists that have high activity on acid-sensing ion channels, but low activity on the G-protein-linked receptor for NPFF. These selective agonists and antagonists will enable us to dissect the separate contribution of each pathway to pain modulation.